1. Field of the Invention
The present invention relates to the field of drug therapy and provides the new use of 2xe2x80x2,2xe2x80x2-difluoronucleosides for the manufacture of compositions for immunosuppressive therapy and new pharmaceutical compositions and products for the treatment of the human and animal body.
2. State of the Art
The suppression of the reactivity of the immune system by immunosuppressive therapy is of major medical importance in the prevention of allograft rejection in transplant patients and in the treatment of autoimmune diseases. Over the past years a limited number of new drugs suitable for use in immunosuppressive therapy such as cyclosporin A, tacrolimus, mycophenolate mofetil, daclizumab and rapamycin have been developed.
There is still a vital need to develop more effective and tolerable methods of treating autoimmune diseases and of preventing allograft rejection in transplant patients. The present invention therefore seeks to provide new pharmaceutical compositions and products for use in this therapeutic area.
2xe2x80x22xe2x80x2-difluoronucleosides have been shown to exhibit antiviral effects in vitro (U.S. Pat. No. 4,808,614) and oncolytic activity in standard cancer screens (U.S. Pat. No. 5,464,826). Among these compounds 2xe2x80x2-deoxy-2xe2x80x2,2xe2x80x2-difluorocytidine (gemcitabine, dFdC) has been studied extensively with regard to its oncolytic activity. Kaye, J. Clin. Oncol. 12, 1527 (1994). Based on the results of these studies gemcitabine hydrochloride has received regulatory approval in more than 50 countries for treatment of non-small cell lung cancer and/or pancreatic cancer. Further studies for treatment of breast, bladder and ovarian cancer with gemcitabine are underway.
The present invention provides the use of a compound of the formula I 
wherein:
R1 is a base defined by one of the formulae 
R2 is hydrogen, C1-C4 alkyl, bromo, fluoro, chloro or iodo;
or a pharmaceutically-acceptable salt thereof for the manufacture of a medicament for immunosuppressive therapy of the human or animal body.
The present invention is further directed to the use of a compound of formula I for the manufacture of a medicament for treating auto-immune diseases in humans and animals.
The present invention also provides the use of a compound of formula I for the manufacture of a medicament for suppressing rejection of transplants in humans and animals, preferably for suppressing rejection of bone marrow transplants, cardiac transplants, cornea transplants, intestine transplants, liver transplants, lung transplants, pancreas transplants, renal transplants and skin transplants.
In another aspect of the invention the compound of formula I is used for the manufacture of a medicament for the treatment of a disease or condition selected from: acne rosacea, acrodermatitis continua, actinic reticuloid, AIDS, alopecia, Alport""s syndrome, amyotrophic lateral sclerosis, aphthous stomatitis, red-cell aplasia, aplastic anemia, asthma, atopic dermatitis, autoimmune enteropathy, Behcet""s syndrome, bullous erythema multiforme, bullous pemphigoid, biliary cirrhosis, corneal melting syndrome, Crohn""s disease, dermatitis herpetiformis, dermatomyositis, diabetes mellitus, Duchenne muscular dystrophy, eczema, epidermolysis bullosa, erythema nodosum leprosum, familial hemophagocytic lymphohistiocytosis, Felty""s syndrome, granuloma annulare, Grave""s ophthalmopathy, hemolytic anemia, hemophilia, hepatitis, ichthyosis, inflammatory bowel disease, interstitial cystitis, interstitial lung disease, Keratoconjunctivitis, Langerhans cell histiocytosis, T-cell leukemias, B-cell leukemias, lymphomas, lichen planus, macrophage activation syndrome, Mooren""s ulcer, morphea, multiple sclerosis, myasthenia gravis, nephropathy, nephrotic syndrome, palmo-plantar pustulosis, pemphigus, persistent photosensitivity, pityriasis rubra pilaris, polymyositis, psoriasis, psoriatic arthritis, pulmonary fibrosis, pyoderma gangrenosum, reticular erythematous mucinosis, rheumatoid arthritis, sarcoidosis, scleritis, scleroderna, serpiginous choroiditis, Sjogren""s syndrome, sprue, Sweet""s syndrome, systemic lupus erythematosus, systemic sclerosis, thrombocytopenia, toxic epidermal necrolysis, ulcerative colitis, uveitis, Weber-Christian disease, drug-induced Weber-Christian panniculitis, Wegener granulomatosis.
Preferably, 2xe2x80x2-deoxy-2xe2x80x2,2xe2x80x2-difluorocytidine of the formula II 
or a pharmaceutically-acceptable salt thereof is employed as the compound for above uses. Preferably, the pharmaceutically-acceptable salt employed is the hydrochloride.
The present invention is also directed to the use of gemcitabine hydrochloride in combination with one or more of cyclosporin A, tacrolimus, mycophenolate mofetil, daclizumab, rapamycin and one or more corticosteroid(s).
Pharmaceutical compositions in unit dose form comprising from 1 to 10 mg of gemcitabine hydrochloride and a pharmaceutically-acceptable carrier, diluent or excipient therefor are provided as another aspect of the invention.
The present invention further provides pharmaceutical compositions comprising a compound of formula I or a pharmaceutically-acceptable salt thereof; one or more of cyclosporin A, tacrolimus, mycophenolate mofetil, daclizumab, rapamycin and one or more corticosteroid(s); and a pharmaceutically-acceptable carrier, diluent or excipient therefor.
Pharmaceutical products containing a compound of formula I or a pharmaceutically-acceptable salt thereof and one or more of cyclosporin A, tacrolimus, mycophenolate mofetil, daclizumab, rapamycin and one or more corticosteroid(s) in combination for simultaneous, separate or sequential use for therapy of the human or animal body are provided as yet another aspect of the present invention.
Preferably, 2xe2x80x2-deoxy-2xe2x80x2,2xe2x80x2-difluorocytidine of formula II or a pharmaceutically-acceptable salt thereof is employed as the compound for the pharmaceutical compositions and pharmaceutical products of the present invention. Preferably, the pharmaceutically-acceptable salt employed is the hydrochloride.